Previous studies have demonstrated that neurotransmission in the rat septohippocampal cholinergic system, which has been implicated in memory functions, undergoes adaptive changes in response to stressful stimuli. During aging, many neurons in this system degenerate and may cause memory loss. It is possible that hyper-reactivity to stressful stimuli can also accelerate neuron degeneration in this system. Our aim in this project is to learn: (a) whether or not the characteristic, stress-induced adaptive changes in cholinergic neurons are altered in rats; (b) how age-related changes in neurotransmitter systems that converge in the septum influence the septohippocampal cholinergic system; (c) how age-related changes in the regulation of the glucocorticoid hormonal system affect the septohippocampal cholinergic system; and (d) how stress-induced changes are in specific stress-responsive proteins, including polyamine metabolism, are involved in neuronal function. The results so far indicate that age- related degeneration of cholinergic neurons is accompanied by compensatory changes in their neighboring neurons to prevent the loss of cholinergic neurotransmission, and that high glucocorticoid levels can accelerate the degeneration rate of cholinergic neurons. Studies are in progress to further pursue these objectives. Reactive changes in neurotransmission are not limited to cholinergic neurons. It is conceivable that within a given responsive neuronal network, several components react to create a new state of activity. Indeed, our recent studies indicate that glutamatergic neurons increase their activity in response to stress in a region selective manner. Thus, within the septal-hippocampal-septal circuit, both cholinergic and glutamatergic neurons are activated in response to stress. This activation does not appear to be secondary to the activation of the hypothalamic-pituitary-adrenocortical axis and rising levels of glucocorticoids. Rather, it is probably dependent on the activation of ascending neuronal inputs such as dopamine neurons that terminate in the septum. More recent findings indicate the involvement of polyamines in the stress response.